Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.5.1.1 (asparaginase)
 2,695 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

L-asparaginase is one of the most important agent used in multidrug chemotherapy regimens in the treatment of malignancies which derive from lymphoid system (acute lymhoblastic leukemias and non-hodgkin lymphoma). L-asparaginase leads to enzymatic cleavage of L-asparagine (amino acid essential for lymphoblasts' growth) to ammonia and L-aspartic acid, what results in depletion of L-asparagine in a serum and cerebrospinal fluid, and finally leads to destruction of lymphoblasts, which lack ability of endogenic L-asparagine production. In the course of L-asparaginase therapy severe side effects could be observed such as: coagulation disturbances, acute pancreatitis, anaphilactic shock and other types of allergic reaction, as well as liver and CNS failure. Monitoring of L-asparaginase activity in serum is recomended in order to optimalize therapy with L-asparaginase and reducing risk of severe side effects. Continuous assessment of L-asparaginase activity during therapy gives also opportunity to detect asymptomatic inactivation of L-ASPA - so called "silent inactivation", which is cused by production of antibodies against xenogenic protein, especcialy in IgG class. This process leads to shortening of half-life of L-ASPA. The paper shows presently available monitoring methods during therapy with L-ASPA, with all their pros and cons.
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PMID:[Significance of L-asparaginase activity and biochemical parameters evaluation in children with acute lymphoblastic leukemia]. 1689

Asparaginase is a key component of the chemotherapy protocols used in the treatment of acute lymphoblastic leukemia (ALL). The current treatment protocols are remarkable in that childhood ALL cure rates are approaching 85%. As the name implies, asparaginase catalyzes the deamination of asparagine to aspartic acid. What is not generally realized is that asparaginase also catalyzes, essentially to the same extent, the removal of the amide nitrogen from glutamine to form glutamic acid. Glutamine is a required substrate for three enzymes involved in the de novo synthesis of purine nucleotides and two enzymes involved in the de novo synthesis of pyrimidine nucleotides. In this review, the specific roles of glutamine in the de novo synthesis of nucleotides are defined and an appropriate explanation for the cell cycle arrest and cytotoxicity induced in proliferating malignant lymphoblasts by asparaginase treatment is provided.
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PMID:Critical roles of glutamine as nitrogen donors in purine and pyrimidine nucleotide synthesis: asparaginase treatment in childhood acute lymphoblastic leukemia. 1709 64

The discovery of the tumor-inhibitory properties of asparaginase (ASNase) began in the early 1950s with the observation that guinea pig serum-treated lymphoma-bearing mice underwent rapid and often complete regression. About 4000 cases of acute lymphoblastic leukemia (ALL) are diagnosed very year in the US and many more through out the world. The majority of these cases are in children and young adults, making ALL the most common form of malignancy in these age groups. The treatment protocols of ALL are complex and use 6-12 drugs. Consequently, the improvement in the protocol design has improved significantly the success rate for long-term event-free survival in the past 20-30 years, which is now approximately 75% for patients afflicted with the higher risk ALL features and just above this percentage for patients with standard or good features. Despite this success, approximately 15% of patients die from ALL, making leukemic relapse the most common cause of treatment failure in pediatric oncology. ASNases have been the cornerstone of ALL therapies since the late 1970s. Native or pegylated L-asparaginase (ASNase or PEG-ASNase) are highly specific for the deamination of L-asparagine (Asn) to aspartic acid and ammonia. Depletion of Asn leads to a nutritional deprivation and inhibition of protein biosynthesis, resulting in apoptosis in T-lymphoblastic leukemias, which require Asn from external sources. The reactions of the host exposed to repeated ASNase treatments as well as the up-regulation of the mammalian enzymes to overcome the ASN-depletion toxic condition are of significant importance and may make us relearn the lessons on this important antileukemic drug.
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PMID:Asparaginase (native ASNase or pegylated ASNase) in the treatment of acute lymphoblastic leukemia. 1771 65

Potentially toxic acrylamide is largely derived from heat-induced reactions between the amino group of the free amino acid asparagine and carbonyl groups of glucose and fructose in cereals, potatoes, and other plant-derived foods. This overview surveys and consolidates the following dietary aspects of acrylamide: distribution in food originating from different sources; consumption by diverse populations; reduction of the acrylamide content in the diet; and suppression of adverse effects in vivo. Methods to reduce adverse effects of dietary acrylamide include (a) selecting potato, cereal, and other plant varieties for dietary use that contain low levels of the acrylamide precursors, namely, asparagine and glucose; (b) removing precursors before processing; (c) using the enzyme asparaginase to hydrolyze asparagine to aspartic acid; (d) selecting processing conditions (pH, temperature, time, processing and storage atmosphere) that minimize acrylamide formation; (e) adding food ingredients (acidulants, amino acids, antioxidants, nonreducing carbohydrates, chitosan, garlic compounds, protein hydrolysates, proteins, metal salts) that have been reported to prevent acrylamide formation; (f) removing/trapping acrylamide after it is formed with the aid of chromatography, evaporation, polymerization, or reaction with other food ingredients; and (g) reducing in vivo toxicity. Research needs are suggested that may further facilitate reducing the acrylamide burden of the diet. Researchers are challenged to (a) apply the available methods and to minimize the acrylamide content of the diet without adversely affecting the nutritional quality, safety, and sensory attributes, including color and flavor, while maintaining consumer acceptance; and (b) educate commercial and home food processors and the public about available approaches to mitigating undesirable effects of dietary acrylamide.
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PMID:Review of methods for the reduction of dietary content and toxicity of acrylamide. 1862 52

Bacterial L-asparaginases are enzymes that catalyze the hydrolysis of l-asparagine to aspartic acid. For the past 30 years, these enzymes have been used as therapeutic agents in the treatment of acute childhood lymphoblastic leukemia. Their intrinsic low-rate glutaminase activity, however, causes serious side-effects, including neurotoxicity, hepatitis, coagulopathy, and other dysfunctions. Erwinia carotovora asparaginase shows decreased glutaminase activity, so it is believed to have fewer side-effects in leukemia therapy. To gain detailed insights into the properties of E. carotovora asparaginase, combined crystallographic, thermal stability and cytotoxic experiments were performed. The crystal structure of E. carotovoral-asparaginase in the presence of L-Asp was determined at 2.5 A resolution and refined to an R cryst of 19.2 (R free = 26.6%) with good stereochemistry. Cytotoxicity measurements revealed that E. carotovora asparaginase is 30 times less toxic than the Escherichia coli enzyme against human leukemia cell lines. Moreover, denaturing experiments showed that E. carotovora asparaginase has decreased thermodynamic stability as compared to the E. coli enzyme and is rapidly inactivated in the presence of urea. On the basis of these results, we propose that E. carotovora asparaginase has limited potential as an antileukemic drug, despite its promising low glutaminase activity. Our analysis may be applicable to the therapeutic evaluation of other asparaginases as well.
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PMID:Structural and functional insights into Erwinia carotovora L-asparaginase. 1864 44

A novel assay for the determination of l-asparaginase activity in human plasma is described that is based on the HPLC quantitation of l-aspartic acid produced during enzyme incubation. Methods for monitoring l-asparagine depletion are also described. Chromatography of l-aspartic acid, l-asparagine and l-homoserine (the internal standard) involved derivatization with o-pthaldialdehyde, then separation from other amino acids on a Phenomenex Luna C(18) column using a 1 mL/min flow rate and a mobile phase consisting of di-potassium hydrogen orthophosphate propionate buffer, pH 6, with 10% methanol and 10% acetonitrile. Fluoresence detection was at excitation/emission wavelengths of 357/455 nm. Under these conditions l-aspartic acid, l-asparagine and l-homoserine had retention times of 3.5, 9.8 and 17.7 min, respectively. The l-asparaginase assay was linear from 0.1 to 10 U/mL activity and interday precision and accuracy were less than 13%. The limit of quantitation was approximately 0.03 U/mL. The assay utility was established in 12 children who received E. coli l-asparaginase as treatment for acute lymphoblastic leukaemia.
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PMID:An isocratic fluorescence HPLC assay for the monitoring of l-asparaginase activity and l-asparagine depletion in children receiving E. colil-asparaginase for the treatment of acute lymphoblastic leukaemia. 1882 71

L-asparaginase is a hydrolase that catalyzes the conversion of L-asparagine--an endogenous amino acid necessary for the function of some neoplastic cells, such as lymphoblasts. In most human cells deficiency of L-asparagine can be compensated by alternative synthesis pathway through which L-asparagine is produced from aspartic acid and glutamine by asparagine synthethase. Depletion of L-asparagine from plasma by L-asparaginase results in inhibition of RNA and DNA synthesis with the subsequent blastic cell apoptosis. Owing to the unique anti-cancer mechanism of action, L-asparaginase has been introduced to the multi drug chemotherapy in children and adults with acute lymphoblastic leukemia, which has contributed to significant improvement of therapy outcomes and to achieve complete remission in about 90% of patients. Notwithstanding its high therapeutic efficacy, L-asparaginase can increase the risk of thrombosis. Inhibition of protein synthesis causes most complications observed during treatment with a native and pegylated form of L-asparaginase, including impaired functions of liver, kidneys or central nervous system. Thrombotic events occur as a result of inhibited synthesis of anticoagulant proteins (mainly antithrombin). Coagulopathy has been observed in 1.1-4% of patients treated with the pegylated L-asparaginase and in 2.1-15% of those receiving its native form. In this paper approaches to optimize the therapy with L-asparaginase have been discussed.
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PMID:Use of L-asparaginase in acute lymphoblastic leukemia: recommendations of the Polish Adult Leukemia Group. 1914 May 71

Asparaginase, an enzyme that hydrolyzes asparagine to aspartic acid, presents a potentially very effective means for reducing acrylamide formation in foods via removal of the precursor, asparagine, from the primary ingredients. An extracellular asparaginase amenable to industrial production was cloned and expressed in Aspergillus oryzae . This asparaginase was tested in a range of food products, including semisweet biscuits, ginger biscuits, crisp bread, French fries, and sliced potato chips. In dough-based applications, addition of asparaginase resulted in reduction of acrylamide content in the final products of 34-92%. Enzyme dose, dough resting time, and water content were identified as critical parameters. Treating French fries and sliced potato chips was more challenging as the solid nature of these whole-cut products limits enzyme-substrate contact. However, by treating potato pieces with asparaginase after blanching, the acrylamide levels in French fries could be lowered by 60-85% and that in potato chips by up to 60%.
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PMID:Evaluating the potential for enzymatic acrylamide mitigation in a range of food products using an asparaginase from Aspergillus oryzae. 1938 39

A dough resembling traditional Spanish rosquillas was used as a model to represent classical fried-dough pastry to investigate the effects of asparaginase and heat treatment on amino acid levels and acrylamide mitigation. Wheat-based dough was deep fried at 180 and 200 degrees C for 4, 6, and 8 min. Two recipes were formulated by addition of different asparaginase levels (100 and 500 U/kg flour) to the dough. The temperature/time profile of the frying process, moisture, sugars, amino acids, acrylamide, and some indicators of the Maillard reaction (hydroxymethylfurfural, color, free fluorescence compounds, and browning) were determined to investigate the extent of the reaction and the effect on reactants. At the both levels of asparaginase used, 96-97% of the asparagine present was converted to aspartic acid, and consequently the acrylamide level was very efficiently reduced (up to 90%). The asparaginase also affected the content of glutamine and glutamic acid in dough, resulting in a 37% increase in glutamic acid compared with the untreated sample. Concerning color, browning and Maillard reaction parameters, no significant changes between untreated and enzymatically treated samples were observed, pointing out the potential industrial and domestic enzyme application.
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PMID:Effect of L-asparaginase on acrylamide mitigation in a fried-dough pastry model. 1982 15

Bacterial L-asparaginases have been used in the treatment of childhood acute lymphoblastic leukaemia for over 30 years. Their therapeutic effect is based on their ability to catalyze the conversion of L-asparagine, an essential amino acid in certain tumours, to L-aspartic acid and ammonia. Two L-asparaginases, one from Escherichia coli and the other from Erwinia chrysanthemi, have been widely employed in clinical practice as anti-leukaemia drugs. However, L-asparaginases are also able to cause severe side effects owing to their intrinsic glutaminase activity. Helicobacter pylori L-asparaginase (HpA) has been reported to have negligible glutaminase activity. To gain insight into the properties of HpA, its crystal structure in the presence of L-aspartate was determined to 1.4 A resolution, which is one of the highest resolutions obtained for an L-asparaginase structure. The final structure has an R(cryst) of 12.6% (R(free) = 16.9%) with good stereochemistry. A detailed analysis of the active site showed major differences in the active-site flexible loop and in the 286-297 loop from the second subunit, which is involved in active-site formation. Accordingly, Glu289, Asn255 and Gln63 are suggested to play roles in modulating the accessibility of the active site. Overall, the structural comparison revealed that HpA has greater structural similarity to E. coli L-asparaginase than to any other L-asparaginase, including Er. carotovora L-asparaginase, despite the fact that the latter is also characterized by low glutaminase activity.
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PMID:Structure of Helicobacter pylori L-asparaginase at 1.4 A resolution. 1996 11


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